Asymmetric One‐Pot Sequential Organo‐ and Gold Catalysis for the Enantioselective Synthesis of Dihydropyrrole Derivatives

Abstract

A direct asymmetric one‐pot synthesis of optically active 2,3‐dihydropyrroles from propargylated malononitrile and N‐Boc‐protected (Boc=tert‐butoxycarbonyl) imines is presented. The approach is based on a bifunctional organocatalytic Mannich‐type reaction and a subsequent gold‐catalyzed alkyne hydroamination and isomerization. The compatibility of both catalytic systems is presented and the overall transformation results in good yields (up to 70 %) with high selectivities (endo/exo>10:1) and enantioselectivities (up to 88 % ee). The absolute configuration of the final products is unambiguously established by X‐ray analysis. To highlight the synthetic potential of the accessed heterocyclic compounds, their transformation into 1‐pyrrolines, which represent direct precursors of pyrrolidines, is presented.

Merging Organocatalysis and Gold Catalysis—A Critical Evaluation of the Underlying Concepts

“…[19] This postulate has been confirmed by 31 P NMR studies carried out by us and other research groups. [20][21][22] In such instances there is strong evidence that the addition of strong Brønsted acid additives such as p-toluenesulfonic acid hydrate (pTSA) helps to regenerate the p-acidic Au I species to ensure the smooth operation of its catalytic cycle. [20][21][22] The only exceptions where secondary amine catalysis does not seem to deactivate the Au I catalyst, and hence no Brønsted acid additives are required, are in cooperative catalyzed carbocyclization reactions reported by Kirsch et al [23] and Jørgensen et al [24] However, these reactions are of type A classification (Scheme 3, vide supra) and the actual reason why no deactivation takes place in these cases still remains an enigma.…”

“…Jørgensen et al first demonstrated the combined use of thiourea catalysis and Au I catalysis in a Mannich/hydroamination sequential reaction of type B (Scheme 15). [20] In this protocol, the versatile alkyne-tethered malonodinitrile substrate 64 was utilized together with Boc-protected imines 65. The CÀC bond formation is the stereogenic step, where the bifunctional chincona alkaloid derived thiourea catalyst 69 was employed to catalyze the Mannich-type reaction enantioselectively through hydrogen-bonding interactions to generate 66.…”

Active Conformation in Amine–Thiourea Bifunctional Organocatalysis Preformed by Catalyst Aggregation

“…The present work was inspired by the premise that the knowledge of experimentally determined ground-state conformations in solution helps the completion of the catalytic cycle that considers catalyst self-association. [14] We determined and interpreted the thermodynamically stable conformations of the pure catalyst 1 in solution by analyzing the 1 H NMR spectra in apolar aprotic solvents (Scheme 1). The method relies on the success of limiting the chemical exchange between the different molecular (monomeric, dimeric) states by significantly lowering the tempera- ture.…”

2.16 The Bimolecular and Intramolecular Mannich and Related Reactions

“…166 On treatment of N-Boc aldimine and propargylated malonitrile with 86 followed by with PPh 3 AuNTf 2 , a Mannich reaction and subsequent (Figure 16), which worked efficiently as a catalyst for the Mannich-type reaction of ketene silyl acetal with aldimines, derived from aromatic aldehyde and o-hydroxyaniline. 168 b-Amino-a-alkyl or a-siloxy carboxylates were obtained in preference to the syn-isomer, and the ee of the syn-isomer reached 96% ee (Scheme 136).…”